Synthesis of vidofludimus and its calcium salt

Abstract

The invention relates to the process of preparation of 2-fluoro-4-(3-methoxyphenyl)aniline (3) as an intermediate. Said intermediate 2-fluoro-4-(3-methoxyphenyl)aniline (3) is obtained in a Suzuki coupling reaction from (3-methoxyphenyl)boronic acid (1) and 4-bromo-2-fluoro-aniline (2). The invention further relates to the synthesis of vidofludimus (5) from said intermediate 2-fluoro-4-(3-methoxy-phenyl)aniline (3) and from 1-cyclopentene-1,2-dicarboxylic anhydride (4). The invention further relates to the synthesis of vidofludimus calcium (6) from said vidofludimus (5) and from a calcium salt, preferably Ca(OH)2.

Description

Synthesis of vidofludimus and its calcium salt

[0001] Priority is claimed of European patent application no. 24 170 004.6 that was filed on April 12, 2024.

[0002] The invention relates to the synthesis of 2-fluoro-4-(3-methoxyphenyl)aniline (3) as an intermediate. Said intermediate 2-fluoro-4-(3-methoxyphenyl)aniline (3) is obtained from (3 -methoxy - phenyl)boronic acid (1) and 4-bromo-2 -fluoro-aniline (2). The invention further relates to the synthesis of vidofludimus (5) from said intermediate 2-fluoro-4-(3-methoxyphenyl)aniline (3) and from 1 -cyclo- pentene- 1,2-dicarboxylic anhydride (4). The invention further relates to the synthesis of vidofludimus calcium (6) from said vidofludimus (5) and from a calcium salt, preferably Ca(OH)2.BACKGROUND ART

[0003] Vidofludimus (2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-l-carboxylic acid; [2-(3-fluoro-3’-methoxybiphenyl-4-yl-carbamoyl)-cy clopent- 1-enecarboxylate]; CAS 717824- 30-1) and its physiologically acceptable salts are selective and potent second-generation dihydroorotate dehydrogenase (DHODH) oral immunomodulators being developed for the treatment of several chronic inflammatory diseases, including relapsing-remitting Multiple Sclerosis (RRMS). Vidofludimus calcium salt hydrate is also known as IMU-838 with the following structure:

[0004] Medical uses of vidofludimus or its salts have been described e.g. in WO 2012 / 001151, WO 2016 / 200778, WO 2018 / 177151, WO 2019 / 101888, WO 2021 / 214033, A. Muehler et al., Drugs R&D 2019;19:351, F. Hahn et al., Viruses 2020;12: 1394, Y. Zhu et al., Front. Pharmacol. 2020;l l:590, A. Muehler et al., Eur. J. Drug Metab. Pharmacokinet. 2020;45:557, A. Muehler et al., Mult. Scler. Relat. Disord. 2020;43: 102129, K. Sharma et al., BMJ Open 2022;12:e055205, M.J.G.T. Vehreschild et al., Infect Dis. Ther. 2022; 11:2159, R.J. Fox et al., Ann. Clin. Transl. Neurol. 2922,9:911 , E.J. Carey et al., Hepatol. Commun. 2022;6: 1589, J. Vietor et al. J. Med. Chem. 2023;66:6391 and H. Guo et al., Virol.Sin. 2023; doi.org / 10.1016 / j.virs.2023.11.006.

[0005] WO 2019 / 175396 relates to calcium salt polymorphs as anti-inflammatory, immunomodulatory and anti-proliferatory agent.

[0006] WO 2022 / 214691 Al relates to deuterated compounds and their use as medicaments.

[0007] WO 2003 / 006425 and WO 2012 / 001148 disclose vidofludimus (Example 26) and related compounds. Different synthetic routes are suggested, one of which involves Suzuki aryl coupling of a halogen derivative with an arylboronic acid in accordance with N.E. Leadbeater et al., Tetrahedron 1999;55: 11889. Such Suzuki aryl couplings according to N.E. Leadbeater et al. are mediated by phos- phine-free nickel complexes to overcome the disadvantages of Pd(PPh3)4 that is said to be the most frequently used catalyst for the Suzuki reaction.

[0008] The Suzuki coupling of (3-methoxyphenyl)boronic acid or its boroxine with 4-bromo-2- fluoroaniline towards intermediate 2-fluoro-4-(3-methoxyphenyl)aniline has been described. For example, WO 2008 / 077639 used 6 mol% of tetrakis(triphenylphosphine)palladium as a catalyst with low atom economy in toluene / MeOH under a nitrogen atmosphere. The same catalyst with 1 mol % has been used in J. Zhu et al., J. Med. Chem. 2015 ;58: 1123. WO 2011 / 138665 uses 6 mol% of the same catalyst in dioxane : water (5: 1) and again under a nitrogen atmosphere.

[0009] Additional references describe the synthesis of intermediate 2-fluoro-4-(3-methoxyphenyl)ani- line, however with no experimental details, e.g., Bioorg. Med. Chem. Lett. 2005; 15:4854, J. Med. Chem. 2015;58: 1123, WO 2013 / 056684 or WO 2004 / 056797.

[0010] The use of 4-iodo-2-fluoroaniline has been described in J. Chem. Res. 2019;43: 161, where again triphenylphosphine and bis(dibenzylideneacetone)palladium was used as catalyst with low atom economy. No hint is given to use catalytic amount of atom economic, heterogeneous palladium catalyst (e.g. Pd on charcoal or PdO on charcoal (Pearlman’s catalyst)) or execution the reaction under a non-inert atmosphere, e.g. air. In addition, the described procedures contain no information on the impurity profile and therefore are not suitable for production of this intermediate.

[0011] J. Leban et al., Bioorg. Med. Chem. Lett. 2004;14:55 relates to the discovery of a novel series of DHODH inhibitors by a docking procedure and QSAR refinement. J. Leban et al., Bioorg. Med. Chem. Lett. 2005; 15:4854 relates to SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors. Vidofludimus is mentioned as Example 4. Substituted biarylanilines were obtained by the Suzuki cross-coupling procedure using commercial aromatic boronic acids and halo anilines with Pd and KF in methanol.

[0012] WO 2018 / 177151 discloses the synthesis of the ethoxy analogue (FD6) of vidofludimus.

[0013] There is a demand for economic processes that provide vidofludimus and vidofludimus calcium in high yields as well as at high purity and that can be scaled up.

[0014] It is an object of the invention to provide processes for preparation of vidofludimus and vidoflu- dimus calcium that have advantages compared to the processes of the prior art. The processes should provide vidofludimus and vidofludimus calcium in high yields and at high purity, especially with respect to minimal residual contents of starting materials and solvents. The processes should involve chemicals that do not cause harm to the patients when the vidofludimus and vidofludimus calcium thus obtained is administered to humans.

[0015] The content of (potential genotoxic) impurities in the synthesized intermediates and in the final drug substance should be reduced to a unprecedented amount. Special care needs to be addressed to the following impurities A to E:

[0016] This object has been achieved by the subject-matter of the patent claims.SUMMARY OF THE INVENTION

[0017] The invention relates to the synthesis of 2-fluoro-4-(3-methoxyphenyl)aniline (3) as an intermediate. Said intermediate 2-fluoro-4-(3-methoxyphenyl)aniline (3) is obtained from (3-methoxy- phenyljboronic acid (1) and from 4-bromo-2-fluoro-aniline (2), preferably in a Suzuki coupling reaction:

[0018] The invention further relates to the synthesis of vidofludimus (5) from said intermediate 2- fluoro-4-(3-methoxyphenyl)aniline (3) and from 1 -cyclopentene- 1, 2 -dicarboxylic anhydride (4):

[0019] The invention further relates to the synthesis of vidofludimus calcium (6) from said vidofludimus (5) and from a calcium salt, preferably Ca(OH)2.

[0020] It has been surprisingly found that reaction of (3-methoxyphenyl)boronic acid (1) and 4-bromo- 2-fluoro-aniline (2) provides improved yield and purity of the intermediate 2-fluoro-4-(3-methoxy- phenyl)aniline (3) when the reaction is performed under catalysis of PdO / C, preferably in the presence of ethanol, in particular absolute ethanol; and / or preferably in the presence of an alkali metal carbonate, in particular K2CO3. Work-up can advantageously be achieved by adding THF and water and subsequent crystallization.

[0021] Further, it has been surprisingly found that formation ofthe intermediate 2-fluoro-4-(3-methox- yphenyl)aniline (3) by amidation with l-cyclopentene-l,2-dicarboxylic anhydride (4) provides improved yield and purity of vidofludimus (5) when the reaction is performed in THF. Work-up can advantageously be achieved by adding heptane and subsequent cooling crystallization.

[0022] Still further, it has been surprisingly found that the conversion of vidofludimus (5) with calcium hydroxide into vidofludimus calcium (6) can be achieved at improved yield and purity when it isperformed in aqueous DMSO in the presence of an adsorbent, preferably charcoal. Work-up can advantageously be achieved by adding ethanol and water and subsequent crystallization.DETAILED DESCRIPTION OF THE INVENTION

[0023] Unless expressly stated otherwise, all values expressed as percentages are wt.-% and all values expressed as ppm are ppm by weight (ppmw).

[0024] For the purpose of the specification, "essentially consisting of' means that specific further components can be present, namely those not materially affecting the essential characteristics of the compound or composition. Preferably, "essentially consisting of' means that the content of such further components is at most 1.0 wt.-%, more preferably at most 0.5 wt.-%, still more preferably at most 0.1 wt.-%.

[0025] Vidofludimus (5) refers to the free carboxylic acid (C20H18FNO4, Mr 355.37 g mol1).

[0026] Vidofludimus calcium (6) refers to the hemi calcium salt of vidofludimus, preferably the hydrate thereof (C^HssCaFsNzOio or more precisely CjjH CaFiNsOsVHsO. Mr 784.82 g mol1).

[0027] According to Q3C, FDA, Guidance for Industry, June 2017, Revision 3, the following solvents are categorized as follows:Process for preparation of 2-fluoro-4-(3-methoxyphenyl)aniline (3):

[0028] A first aspect of the invention relates to a process for preparation of 2-fluoro-4-(3-methoxy- phenyl)aniline (3) comprising or consisting of the steps:(ai) providing (3-methoxyphenyl)boronic acid (1);(a2) providing 4-bromo-2-fluoro-aniline (2);(as) reacting (3-methoxyphenyl)boronic acid (1) and 4-bromo-2 -fluoro-aniline (2) to afford 2-fluoro-4- (3-methoxyphenyl)aniline (3):(34) optionally, isolating 2-fluoro-4-(3-methoxyphenyl)aniline (3).

[0029] The (3-methoxyphenyl)boronic acid (1) may be partially present in form of the boroxine (!'), as evident by Karl Fischer titration of the water content. Unless expressly stated otherwise, the (3-meth- oxyphenyl)boronic acid can thus either be present in form of monomer (1) or cyclic trimer (boroxine) (1'):1 r

[0030] Preferably, in step (as) the molar ratio of (3-methoxyphenyl)boronic acid (1) to 4-bromo-2- fluoro-aniline (2) is greater than 1.00; preferably at least 1.01; more preferably within the range from 1.01 to 1.30; still more preferably from 1.01 to 1.05.

[0031] Preferably, in step (ai) (3-methoxyphenyl)boronic acid (1) is provided as a solution or suspension in a solvent; preferably ethanol; more preferably absolute ethanol.

[0032] Preferably, in step (as) 4-bromo-2-fluoro-aniline (2) is provided as a solution or suspension in a solvent; preferably ethanol; more preferably absolute ethanol.

[0033] Preferably, the solution or suspension additionally comprises or essentially consists of a catalyst, preferably a Suzuki coupling catalyst, and optionally a base.

[0034] Preferably, in step (as) (3-methoxyphenyl)boronic acid (1) is added to the solution or suspension.

[0035] Preferably, in step (as) (3-methoxyphenyl)boronic acid (1) is added continuously or in portions during a time period of at least 30 minutes; preferably at least 60 minutes; more preferably at least 90 minutes.

[0036] Preferably, step (as) is performed in the presence of a catalyst, preferably a Suzuki coupling catalyst, comprising palladium; preferably selected from PdO / C, Pd / C and Pd(PPh3)4; more preferably PdO / C.

[0037] Preferably, step (as) is performed in the presence of a base; preferably an inorganic base; more preferably a carbonate; still more preferably an alkali metal carbonate; yet more preferably an alkali metal carbonate selected from K2COs, Na2CO3and Cs2CO3; even more preferably K2COs.

[0038] Preferably, in step (a3) the molar ratio of (3-methoxyphenyl)boronic acid (1) to the base is greater than 1.00; preferably at least 1.05; more preferably at least 1.10; still more preferably within the range of from l.lO to 1.50; yet more preferably from l.lO to 1.20.

[0039] Preferably, step (a3) is performed in a solvent comprising or essentially consisting of ethanol, dimethoxy ethane, water, or any mixture thereof; preferably ethanol; more preferably absolute ethanol.

[0040] Preferably, step (a3) is performed at a temperature above 60°C; more preferably under reflux temperature. The reflux temperature depends upon the solvent and is preferably above 60°C, more preferably above 70°C. Preferred reflux temperatures are within the range of from about 78°C to about 100°C.

[0041] In preferred embodiments, step (a3) is performed- in the presence of a catalyst, preferably a Suzuki coupling catalyst, comprising palladium; preferably selected from PdO / C, Pd / C and Pd(PPh3)4; more preferably PdO / C; and- in a solvent comprising or essentially consisting of ethanol, dimethoxy ethane, water, or any mixture thereof; preferably ethanol; more preferably absolute ethanol.

[0042] In other preferred embodiments, step (a3) is performed- in the presence of a catalyst, preferably a Suzuki coupling catalyst, comprising palladium; preferably selected from PdO / C, Pd / C and Pd(PPh3)4; more preferably PdO / C; and- in the presence of a base; preferably an inorganic base; more preferably a carbonate; still more preferably an alkali metal carbonate; yet more preferably an alkali metal carbonate selected from K2CO3, Na2CO3and Cs2CO3; even more preferably K2CO3.

[0043] In further preferred embodiments, step (a3) is performed- in the presence of a catalyst, preferably a Suzuki coupling catalyst, comprising palladium; preferably selected from PdO / C, Pd / C and Pd(PPh3)4; more preferably PdO / C; and- in the presence of a base; preferably an inorganic base; more preferably a carbonate; still more preferably an alkali metal carbonate; yet more preferably an alkali metal carbonate selected from K2CO3, Na2CC>3 and CS2CO3; even more preferably K2CO3; and- in a solvent comprising or essentially consisting of ethanol, dimethoxy ethane, water, or any mixture thereof; preferably ethanol; more preferably absolute ethanol.

[0044] Preferably, step (34) comprises crystallization of 2-fluoro-4-(3-methoxyphenyl)anilme (3); preferably cooling crystallization.

[0045] Preferably, crystallization is performed from a solution in a solvent comprising or essentially consisting of ethanol, THF, water, or any mixture thereof; preferably from a mixture of ethanol, THF and water.

[0046] Preferably, crystallization is induced by adding seed crystals of 2-fluoro-4-(3-methoxy- phenyl)aniline (3).

[0047] Preferably, the crystals are isolated, e.g. by filtration, and dried, e.g. at elevated temperature and / or under reduced pressure.

[0048] Preferably, step (at) comprises evaporation of solvent, e.g. at elevated temperature and / or under reduced pressure.Process for preparation of vidofludimus (5):

[0049] A further aspect of the invention relates to a process for preparation of vidofludimus (5) comprising or consisting of the steps:(bi) providing 2-fluoro-4-(3-methoxyphenyl)aniline (3);(b2) providing l-cyclopentene-l,2-dicarboxylic anhydride (4);(bi) reacting 2-fluoro-4-(3-methoxyphenyl)aniline (3) with 1 -cyclopentene- 1,2 -dicarboxylic anhydride (4) to afford vidofludimus (5):(b4) optionally, isolating the vidofludimus (5).

[0050] Preferably, step (bi) comprises or consists of the process for preparation of2-fluoro-4-(3-meth- oxyphenyl)aniline (3) according to the invention as described above.

[0051] Preferably, in step (b?) the molar ratio of 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) to 2- fhroro-4-(3-methoxyphenyl)aniline (3) is greater than 1.00; preferably at least 1.01; more preferably at least 1.02; still more preferably within the range of from 1.02 to 1.30; yet more preferably from 1.02 to 1.10.

[0052] Preferably, in step (b2) l-cyclopentene-l,2-dicarboxyhc anhydride (4) is provided as a solution or suspension in a solvent; preferably THF.

[0053] Preferably, in step (bi) 2-fluoro-4-(3-methoxyphenyl)aniline (3) is provided as a solution or suspension in a solvent; preferably THF.

[0054] Preferably, in step (b;) 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) is added to the solution or suspension.

[0055] Preferably, in step (b;,) 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) is added continuously or in portions during a time period of at least 5 minutes; preferably at least 10 minutes; more preferably at least 15 minutes.

[0056] Preferably, in step (b?) a first portion of 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) is added to the solution or suspension; and wherein after crystallization of vidofludimus (5) has commenced, a second portion of 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) is added to the suspension.

[0057] Preferably, step (bs) is performed in a solvent comprising or essentially consisting of THF.

[0058] Preferably, step (bg) is performed at a temperature of from 50°C to 66°C; preferably from 55°C to 65°C.

[0059] Step (b4) is optional.

[0060] Preferably, step (b4) comprises crystallization of vidofludimus (5); preferably cooling crystallization.

[0061] Preferably, crystallization of vidofludimus (5) is performed from a solution in a solvent comprising or essentially consisting of THF, heptane, or a mixture thereof; preferably from a mixture of THF and heptane.

[0062] Preferably, crystallization is induced by adding seed crystals of vidofludimus (5).

[0063] Preferably, the crystals are isolated, e.g. by filtration, and dried, e.g. at elevated temperature and / or under reduced pressure.

[0064] Preferably, step (b4) comprises evaporation of solvent.

[0065] When optional step (b4) is not performed, the reaction mixture obtained in step (b < ) can be subjected to steps (C2), (C3) and optionally (C4) here below without isolation of vidofludimus (5).

[0066] In another aspect, the present invention relates to vidofludimus (5) or a pharmaceutically acceptable salt thereof which is obtainable by the method according to any of the above embodiments.

[0067] In one embodiment, vidofludimus (5) or a pharmaceutically acceptable salt thereof which is obtainable by the method according to any of the above embodiments has:A) a residual content of palladium, determined by ICP-MS, amounting to (i) at least 0.01 ppm and (ii) less than 2.00 ppm; preferably at most 1.50 ppm; more preferably at most 1.00 ppm; still more preferably at most 0.80 ppm; and / orB) a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]car- bamoyl]cyclopentene-l -carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; in each case relative to the total weight of vidofludimus (5); preferably wherein the compound has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppm.

[0068] In one embodiment, vidofludimus (5) or a pharmaceutically acceptable salt thereof which is obtainable by the method according to any of the above embodiments has a content of vidofludimus (5) or a pharmaceutically acceptable salt thereof of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99 00 wt .-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt-%; in each case relative to the total weight of the compound.

[0069] In one embodiment, vidofludimus (5) which is obtainable by the method according to any of the above embodiments has characteristic XRPD peaks (Civ,, irradiation at room temperature) at 10.6±0.2 20, 11.3±O.2 20, 14.2±0.2 20, 21.3±0.2 20, 21.6±0.220, and 26.1±0.2 20.

[0070] In one embodiment, vidofludimus (5) which is obtainable by the method according to any of the above embodiments has additionally one or more characteristic XRPD peaks (Civ,, irradiation at room temperature) selected from 14.5±0.2 20, 19.8±0.2 20, 20.7±0.2 20, 22.6±0.2 20, 23.5±0.2 20, 28.0±0.220, 28.4±0.2 20, and 28.7±0.2 20.Process for preparation of vidofludimus calcium (6):

[0071] Another aspect of the invention relates to a process for preparation of vidofludimus calcium (6) comprising or essentially consisting of the steps:(ci) providing vidofludimus (5);(c2) providing a calcium salt, preferably Ca(OH)2;(eg) reacting vidofludimus (5) with the calcium salt to afford vidofludimus calcium (6); and(C4) optionally, isolating vidofludimus calcium (6).

[0072] Preferably, step (ci) comprises or consists of the process for preparation of vidofludimus (5) according to the invention as described above.

[0073] Preferably, in step (eg) the molar ratio of calcium salt to vidofludimus (5) is greater than 0.50; preferably at least 0.51; more preferably within the range of from 0.51 to 0.80; more preferably within the range of from 0.51 to 0.80; still more preferably from 0.51 to 0.60.

[0074] Preferably, the calcium salt comprises or essentially consists of Ca(OH)2. Alternative calcium salts include but are not limited to CaCIg and CaS©4.

[0075] Preferably, in step (ci) vidofludimus (5) is provided as a solution or suspension in a solvent; preferably DMSO, water or a mixture thereof.

[0076] Preferably, in step (eg) calcium salt is added to the solution or suspension.

[0077] Preferably, step (eg) is performed in a solvent comprising or essentially consisting of DMSO, water or a mixture thereof; preferably a mixture of DMSO and water.

[0078] Preferably,(i) step (eg) is performed in the presence of an adsorbent; or(ii) after step (eg) an adsorbent is added.

[0079] Preferably, the adsorbent comprises or essentially consists of charcoal. Preferably, the adsorbent is capable of adsorbing substances other than vidofludimus (5), e.g. undesired impurities.

[0080] Preferably, step (04) comprises crystallization of vidofludimus calcium (6); preferably cooling crystallization.

[0081] Preferably, crystallization of vidofludimus calcium (6) is performed from a solution in a solvent comprising or essentially consisting of DMSO, water, ethanol, or a mixture thereof; preferably from a mixture of DMSO, water and ethanol.

[0082] Preferably, crystallization is induced by adding seed crystals of vidofludimus calcium (6).

[0083] Preferably, the crystals are isolated, e.g. by filtration, and dried, e.g. at elevated temperature and / or under reduced pressure.

[0084] Preferably, step (C4) comprises evaporation of solvent.

[0085] In another aspect, the present invention relates to vidofludimus calcium (6) which is obtainable by the method according to any of the above embodiments.

[0086] In one embodiment, vidofludimus calcium (6) which is obtainable by the method according to any of the above embodiments has:A) a residual content of palladium, determined by ICP-MS, amounting to (i) at least 0.01 ppm and (ii) less than 2.00 ppm; preferably at most 1.50 ppm; more preferably at most 1.00 ppm; still more preferably at most 0.80 ppm; and / orB) a residual content of impurity (E) (2-[[4-(4-ammo-3-fluoro-phenyl)-2-fluoro-phenyl]car- bamoyl]cyclopentene-l -carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; in each case relative to the total weight of vidofludimus calcium (6); preferably wherein the composition has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppm.

[0087] In one embodiment, vidofludimus calcium (6) which is obtainable by the method according to any of the above embodiments has a content of vidofludimus calcium (6) of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99.00 wt.-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt.-%; in each case relative to the total weight of the compound.Composition of vidofludimus (5) / purity of vidofludimus (5):

[0088] Another aspect of the invention relates to a composition essentially consisting of vidofludimus (5), whichA) has a residual content of palladium, determined by ICP-MS, amounting to(i) at least 0.01 ppm and(ii) at most 10 ppm; preferably at most 5.00 ppm; more preferably less than 2.00 ppm; still more preferably at most 1.50 ppm; yet more preferably at most 1.00 ppm; even more preferably at most 0.80 ppm; and / orB) has a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]car- bamoyl] cyclopentene- 1 -carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; determined by HPLC; in each case relative to the total weight of vidofludimus (5).

[0089] In one embodiment, the composition of vidofludimus (5)A) has a residual content of palladium, determined by ICP-MS, amounting to(i) at least 0.01 ppm and(ii)less than 2.00 ppm; preferably at most 1.50 ppm; more preferably at most 1.00 ppm; still more preferably at most 0.80 ppm; and / orB) has a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]car- bamoyl]cyclopentene-l -carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; determined by HPLC; in each case relative to the total weight of vidofludimus (5).

[0090] Preferably, the composition of vidofludimus (5) has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppm.

[0001] The composition of vidofludimus (5) predominantly consists of vidofludimus (5), but not only of vidofludimus (5), and hence is qualified as a composition. Alternatively, it may be regarded as a compound having a certain degree of purity, or a material. For the purpose of the description, these terms can be used interchangeably.

[0092] Impurity (E) is problematic because it is positive in silico test result, i .e. potentially mutagenic in silico consensus assessment ((Q)SAR models from the Leadscope gentox statistical models).

[0093] It has been unexpectedly found that reaction conditions of the prior art may favor dimer formation as byproducts. It has now been surprisingly found that by the process according to the invention, such dimer formation can be controlled and suppressed thereby leading to very low residual contents of dimer and impurity (E), if any.

[0094] Preferably, the composition of vidofludimus (5) has a content of vidofludimus (5) of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99.00 wt.-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt.-%; in each case relative to the total weight of the composition.

[0095] Preferably, the composition of vidofludimus (5) has one or more of the following residual contents of starting materials or byproducts, in each case determined by HPLC and in each case relative to the total weight of vidofludimus (5):(i) 2-fluoroaniline: <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt.-%; and / or(ii) 2-fluoro-4-(3-methoxyphenyl)aniline (3): <0.003 wt.-%; preferably <0.002 wt.-%; and / or(iii) 4-bromo-2-fluoroaniline (2): <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt- %; and / or(iv) cy clopent- l-ene-l,2-dicarboxylic acid: <0.15 wt.-%; preferably <0.05 wt.-%; more preferably <0.016 wt.-%; still more preferably <0.014 wt.-%.

[0096] More preferably, the composition of vidofludimus (5) has one or more of the following residual contents of starting materials or byproducts, in each case determined by HPLC and in each case relative to the total weight of vidofludimus (5):(i) 2-fluoroaniline: <0.003 wt.-%; preferably <0.002 wt.-%;(ii) 2-fluoro-4-(3-methoxyphenyl)aniline (3): <0.002 wt.-%;(iii) 4-bromo-2-fluoroaniline (2): <0.002 wt.-%; and / or(iv) cy clopent- l-ene-l,2-dicarboxylic acid: <0.016 wt.-%; preferably <0.014 wt.-%.

[0097] Preferably, the composition of vidofludimus (5) has a total content of impurities of at most 0.5 wt.-%, in each case determined by HPLC and in each case relative to the total weight of vidofludimus (5).

[0098] Preferably, the composition of vidofludimus (5) has a water content of at most 5.0 wt.-%, determined by Karl Fischer titration.

[0099] Preferably, the composition of vidofludimus (5) has one or more of the following residual contents of solvents, in each case determined by GC and in each case relative to the total weight of vidofludimus (5):(i) ethanol: <5000 ppm; preferably <500 ppm; more preferably <50 ppm; still more preferably <10 ppm; and / or(ii) heptane: <5000 ppm; preferably <500 ppm; more preferably <160 ppm; and / or(iii) THF: <720 ppm; preferably <500 ppm; more preferably <400 ppm; still more preferably <300 ppm; and / or(iv) DMSO: <5000 ppm.

[0100] More preferably, the composition of vidofludimus (5) has one or more of the following residual contents of solvents, in each case determined by GC and in each case relative to the total weight of vidofludimus (5):(i) ethanol: <10 ppm;(ii) heptane: <160 ppm; and / or(iii) THF: <400 ppm; preferably <300 ppm.

[0101] Preferably, the composition of vidofludimus (5) has one or more of the following residual contents of metals, in each case determined by ICP-MS and in each case relative to the total weight of vidofludimus (5):(i) arsenic (As): <1.5 ppm; and / or(ii) cadmium (Cd): <0.5 ppm; and / or(iii) lead (Pb): <0.5 ppm; and / or(iv) mercury (Hg): <3.0 ppm; and / or(v) cobalt (Co): <5.0 ppm; and / or(vi) nickel (Ni): <20 ppm; and / or(vii) vanadium (V): <10 ppm.

[0102] Preferably, the composition of vidofludimus (5) (material) has characteristic XRPD peaks (Cu2a irradiation at room temperature) at 10.6±0.220, 11.3±0.2 20, 14.2±0.2 20, 21.3±0.2 20, 21.6±0.2 20, and 26.1±0.2 20. Preferably, the composition additionally has one or more characteristic XRPD peaks (Cu2« irradiation at room temperature) selected from 14.5±0.2 20, 19.8±0.2 20, 20.7±0.2 20, 22.6±0.2 20, 23.5±0.220, 28.0±0.220, 28.4±0.2 20, and 28.7±0.2 20.

[0103] Preferably, the composition of vidofludimus (5) has characteristic XRPD peaks (Cu2a irradiation at room temperature) comprising at least 3 of the following peaks: 10.6±0.220, 11.3±0.2 20, 14.2±0.2 20, 21.3±0.2 20, 21.6±0.2 20, and 26.1±0.2 20. Preferably, the composition additionally has one or more characteristic XRPD peaks (Cuza irradiation at room temperature) selected from 14.5±0.2 20, 19.8±0.220, 20.7±0.2 20, 22.6±0.2 20, 23.5±0.2 20, 28.0±0.2 20, 28.4±0.2 20, and 28.7±0.2 20.

[0104] Preferably, the composition of vidofludimus (5) has characteristic XRPD peaks (Cu2a irradiation at room temperature) comprising at least 4 of the following peaks: 10.6±0.220, 11.3±0.2 20, 14.2±0.2 20, 21.3±0.2 20, 21.6±0.2 20, and 26.1±0.2 20. Preferably, the composition additionally has one ormore characteristic XRPD peaks (Cibu irradiation at room temperature) selected from 14.5±0.2 20, 19.8±0.220, 20.7±0.2 20, 22.6±0.2 20, 23.5±0.2 20, 28.0±0.2 20, 28.4±0.2 20, and 28.7±0.2 20.

[0105] Preferably, the composition of vidofludimus (5) has characteristic XRPD peaks (Cu2airradiation at room temperature) comprising at least 5 of the following peaks: 10.6±0.220, 11.3±0.2 20, 14.2±0.2 20, 14.5±0.2 20, 19.8±0.2 20, 20.7±0.2 20, 21.3±0.2 20, 21.6±0.2 20, 22.6±0.2 20, 23.5±0.2 20, 26.1±0.220, 28.0±0.2 20, 28.4±0.2 20, and 28.7±0.2 20.

[0106] Preferably, the composition of vidofludimus (5) is obtainable by the process for preparation of vidofludimus (5) according to the invention as described above.Composition of vidofludimus calcium (6) / purity of vidofludimus calcium (6):

[0107] Another aspect of the invention relates to a composition essentially consisting of vidofludimus calcium (6), which has a content of vidofludimus calcium (6) of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99.00 wt.-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt.-%; in each case relative to the total weight of the composition.

[0108] The composition of vidofludimus calcium (6) predominantly consists of vidofludimus calcium (6), but not only of vidofludimus calcium (6), and hence is qualified as a composition. Alternatively, it may be regarded as a compound having a certain degree of purity, or a material. For the purpose of the description, these terms can be used interchangeably.

[0109] Preferably, the composition of vidofludimus calcium (6) has a residual content of palladium, determined by ICP-MS and in each case relative to the total weight of vidofludimus calcium (6), amounting to (i) at least 0.01 ppm and (li) at most 10 ppm; preferably at most 5.00 ppm; more preferably less than 2.00 ppm; still more preferably at most 1.50 ppm; yet more preferably at most 1.00 ppm; even more preferably at most 0.80 ppm.

[0110] Preferably, the composition of vidofludimus calcium (6) has a content of arsenic (As), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6), of 0.00 to <1.5 ppm.

[0111] Preferably, the composition of vidofludimus calcium (6) has a content of cadmium (Cd), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <0.5 ppm.

[0112] Preferably, the composition of vidofludimus calcium (6) has a content of lead (Pb), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <0.5 ppm.

[0113] Preferably, the composition of vidofludimus calcium (6) has a content of mercury (Hg), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <3.0 ppm.

[0114] Preferably, the composition of vidofludimus calcium (6) has a content of cobalt (Co), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <5.0 ppm.

[0115] Preferably, the composition of vidofludimus calcium (6) has a content of nickel (Ni), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6), of 0.00 to <20 ppm.

[0116] Preferably, the composition of vidofludimus calcium (6) has a content of vanadium (V), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <10 ppm.

[0117] Preferably, the composition of vidofludimus calcium (6) has a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]carbamoyl]cyclopentene-l-carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt- %; in each case relative to the total weight of vidofludimus calcium (6); preferably wherein the composition has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppm.

[0118] Preferably, the composition of vidofludimus calcium (6) has a residual content of 2-fluoroan- iline, determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt.-%.

[0119] Preferably, the composition of vidofludimus calcium (6) has a residual content of 2-fluoro-4-(3- methoxyphenyl)aniline (3), determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.003 wt.-%; preferably <0.002 wt.-%.

[0120] Preferably, the composition of vidofludimus calcium (6) has a residual content of 4-bromo-2- fluoroaniline (2), determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt-%.

[0121] Preferably, the composition of vidofludimus calcium (6) has a residual content of cyclopent-1- ene-l,2-dicarboxylic acid, determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.15 wt.-%; preferably <0.05 wt.-%; more preferably <0.016 wt.-%; still more preferably <0.014 wt.-%.

[0122] Preferably, the composition of vidofludimus calcium (6) has a total content of impurities of at most 0.5 wt.-%, in each case determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6).

[0123] Preferably, the composition of vidofludimus calcium (6) has a water content of at most 5.0 wt- %, determined by Karl Fischer titration and relative to the total weight of vidofludimus calcium (6).

[0124] Preferably, the composition of vidofludimus calcium (6) has a residual content of ethanol, determined by GC and in each case relative to the total weight of vidofludimus calcium (6), of <5000 ppm; preferably <500 ppm; more preferably <50 ppm; still more preferably <10 ppm.

[0125] Preferably, the composition of vidofludimus calcium (6) has a residual content of heptane, determined by GC and in each case relative to the total weight of vidofludimus calcium (6), of <5000 ppm; preferably <500 ppm; more preferably <160 ppm.

[0126] Preferably, the composition of vidofludimus calcium (6) has a residual content of THF, determined by GC and in each case relative to the total weight of vidofludimus calcium (6), of <720 ppm; preferably <500 ppm; more preferably <400 ppm; still more preferably <300 ppm.

[0127] Preferably, the composition of vidofludimus calcium (6) has a residual content of DMSO, determined by GC and relative to the total weight of vidofludimus calcium (6), of <5000 ppm.

[0128] Preferably, the composition of vidofludimus calcium (6) is obtainable by the process for preparation of vidofludimus calcium (6) according to the invention as described above.Pharmaceutical composition:

[0129] Another aspect of the invention relates to a pharmaceutical composition comprising- (i) the composition of vidofludimus (5) according to the invention as described above or (ii) the composition of vidofludimus calcium (6) according to the invention as describe above, and- at least one pharmaceutically acceptable carrier or excipient.

[0130] The term "pharmaceutically acceptable carrier" as used herein indicates that the carrier is approved or recognized for use in animals, and more particularly in humans, i.e. it is not toxic to the host or patient. In addition a carrier of choice will not interfere with the effectiveness of the biological activity of the active ingredient. The term "carrier" refers to any auxiliary material necessary for the particular mode of administration of choice and includes e.g. solvents, diluents, excipients or other additives with which the compound of the invention is administered. Typically used diluents pharmaceutical carriers include sterile liquids, such as aqueous solutions and oils (e.g. of petroleum, animal, vegetable or synthetic origin), e.g. peanut oil, soybean oil, mineral oil, sesame oil and the like. Typically used aqueous liquids include water, saline solutions, aqueous dextrose and glycerol solutions and the like. Suitable pharmaceutical excipients include citric acid, ascorbic acid, starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0131] The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his / her expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used.Analytical methods:

[0132] In one embodiment, the content of elemental impurities (e.g. palladium) is performed by inductively coupled plasma-mass spectrometry (ICP-MS) screening analogue USP <232>, <233>.

[0133] In one embodiment, the water content is determined by the U SP <921> method.

[0134] In one embodiment, residual solvent determination (ethanol, tetrahydrofuran, n-heptane and dimethyl sulfoxide) in vidofludimus (5) and vidofludimus calcium (6) is determined by gas chromatography with headspace injection (GC) with the method as outlined below:GC Agilent 6890N, 7890A or 8890 or equivalentColumn CP-Volamine, 60 m x 0.32 mm (Agilent) or equivalentDetector FIDCarrier gas HeliumGC parameters 280°C detector temperature 180°C inlet temperatureTemperature program 40°C (2 min), 10°C / min to 180°C (1 min)Headspace parameters Oven temperature: 80°CInjection volume: 1 mLStandard solutions Solutions in DMF at approx. 1.00 mg / mL ethanol, 1.00 mg / mL dimethyl sulfoxide, 0.14 mg / mL THF, 1.00 mg / mL heptaneSample solution 200 mg sample dissolved in 1 mL DMF

[0135] In one embodiment, organic impurities in vidofludimus (5) and vidofludimus calcium (6) are determined by HPLC using the following chromatographic conditions:Column Phenomenex Synergi Fusion RP 80 A 250 x 4.6 mm; 4 pm or equivalentSecurity guard Phenomenex Synergi Fusion RP 4 x 3.0 mm or equivalent (as required)Eluent A 5 mM KH2PO4, pH 1.5Eluent B Acetonitrile (ACN)Detector UV / VIS, 262 nm;238 nm for the related substance 4-bromo-2-fluoroaniline (2)

[0137] Particularly preferred embodiments of the invention are compiled as clauses hereinafter:Clause 1: A process for preparation of vidofludimus calcium (6) comprising the steps: (b) providing vidofludimus (5); (c) reacting vidofludimus (5) with a calcium salt to afford vidofludimus calcium (6).Clause 2: A process for preparation of vidofludimus (5) comprising the steps: (bi) providing 2-fluoro- 4-(3-methoxyphenyl)aniline (3); (b2) providing 1 -cyclopentene- 1,2-dicarboxylic anhydride (4); (bs)re- acting 2-fluoro-4-(3-methoxyphenyl)aniline (3) with 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) to afford vidofludimus (5):Clause 3 : A process for preparation of the intermediate 2-fluoro-4-(3-methoxyphenyl)aniline (3) comprising the steps: (ai) providing (3-methoxyphenyl)boronic acid (1); (a2) providing 4-bromo-2-fluoro- aniline (2); (as) reacting (3-methoxyphenyl)boronic acid (1) and 4-bromo-2-fluoro-aniline (2) to afford 2-fluoro-4-(3 -methoxyphenyl)aniline (3) :1 2 3.Clause 4: The process for preparation of vidofludimus (5) according to clause 2, wherein 2-fluoro-4- (3-methoxyphenyl)aniline (3) in step (bi) is provided by means of the method as defined in clause 3.Clause 5: The process for preparation of vidofludimus calcium (6) according to clause 1, wherein vidofludimus (5) in step (b) is provided by means of the method as defined in clause 2.Clause 6: The process for preparation of vidofludimus calcium (6) according to clause 1, wherein vidofludimus (5) in step (b) is provided by means of the method as defined in clause 4.Clause 7: The process according to any of clauses 3, 4 or 6, wherein the molar ratio of (3-methoxy- phenyl)boronic acid (1) to 4-bromo-2-fluoro-aniline (2) is greater than 1.00; preferably at least 1.01; more preferably within the range from 1.01 to 1.30; still more preferably from 1.01 to 1.05.Clause 8: The process according to any of clauses 3, 4, 6 or 7, wherein step (a3) is performed in the presence of a catalyst, preferably Suzuki coupling catalyst, comprising palladium; preferably selected from PdO / C, Pd / C and (PPh’APd: more preferably PdO / C.Clause 9: The process according to any of clauses 3, 4, or 6 to 8, wherein step (a3) is performed in the presence of a base; preferably an inorganic base; more preferably a carbonate; still more preferably an alkali metal carbonate; yet more preferably an alkali metal carbonate selected from K2CO3, Na2COs and CS2CO3; even more preferably K2CO3.Clause 10: The process according to clause 9, wherein the molar ratio of (3-methoxyphenyl)boronic acid (1) to the base is greaterthan 1.00; preferably at least 1.05; more preferably at least 1.10; still more preferably within the range of from 1.10 to 1.50; yet more preferably from 1. 10 to 1.20.Clause 11: The process according to any of clauses 3, 4, or 6 to 10, wherein step (a3) is performed in a solvent comprising or essentially consisting of ethanol, dimethoxy ethane, water, or any mixture thereof; preferably ethanol; more preferably absolute ethanol.Clause 12: The process according to any of clauses 2 or 4 to 6, wherein the molar ratio of 1-cyclopen- tene-1, 2 -dicarboxylic anhydride (4) to 2-fluoro-4-(3-methoxyphenyl)aniline (3) is greater than 1.00; preferably at least 1.01; more preferably at least 1.02; still more preferably within the range of from 1.02 to 1.30; yet more preferably from 1.02 to 1.10.Clause 13: The process according to any of clauses 2 or 4 to 7, wherein step (b3) is performed in a solvent comprising or essentially consisting of THF.Clause 14: The process according to any of clauses 1, 5 or 6, wherein the molar ratio of calcium salt to vidofludimus (5) is greater than 0.50; preferably at least 0.51; more preferably within the range of from 0.51 to 0.80; still more preferably from 0.51 to 0.60.Clause 15: The process according to any of clauses 1, 5, 6, or 14, wherein the calcium salt comprises or essentially consists of Ca(OH)2.Clause 16: The process according to any of clauses 1, 5, 6, 14 or 15, wherein step (c) is performed in a solvent comprising or essentially consisting of DMSO, water or a mixture thereof; preferably a mixture of DMSO and water.Clause 17: The process according to any of clauses 1, 5, 6 or 14 or 16, wherein (i) step (c) is performed in the presence of an adsorbent; or (ii) after step (c) an adsorbent is added.Clause 18: The process according to clause 17, wherein the adsorbent comprises or essentially consists of charcoal.Clause 19: A composition essentially consisting of vidofludimus (5), which A) has a residual content of palladium, determined by ICP-MS, amounting to (i) at least 0.01 ppm and (ii) less than 2.00 ppm; preferably at most 1.50 ppm; more preferably at most 1.00 ppm; still more preferably at most 0.80 ppm; and / or B) has a residual content of 2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]carbamoyl]cyclo- pentene-1 -carboxylic acid (E) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; in each case relative to the total weight of vidofludimus (5).Clause 20: The composition according to clause 19, which (i) has a content of vidofludimus (5) of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99.00 wt-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt- %; in each case relative to the total weight of the composition; and / or (ii) is obtainable by the process according to any of clauses 1 to 18Clause 21: A pharmaceutical composition comprising the composition according to clause 19 or 20 and at least one pharmaceutically acceptable carrier or excipient.EXAMPLES

[0138] The following examples further illustrate the invention but are not to be construed as limiting its scope.Analytical methods:

[0139] The content of elemental impurities (e.g. palladium) was performed by inductively coupled plasma-mass spectrometry (ICP-MS) screening analogue USP <232>, <233>.

[0140] The water content was determined by the USP <921> method.

[0141] Residual solvent determination (ethanol, tetrahydrofuran, n-heptane and dimethyl sulfoxide) in vidofludimus (5) and vidofludimus calcium (6) was determined by gas chromatography with headspace injection (GC) with the method as outlined below:GC Agilent 6890N, 7890A or 8890 or equivalentColumn CP-Volamine, 60 m x 0.32 mm (Agilent) or equivalentDetector FIDCarrier gas HeliumGC parameters 280°C detector temperature 180°C inlet temperatureTemperature program 40°C (2 min), 10°C / min to 180°C (1 min)Headspace parameters Oven temperature: 80°CInjection volume: 1 mLStandard solutions Solutions in DMF at approx. 1.00 mg / mL ethanol, 1.00 mg / mL dimethyl sulfoxide, 0.14 mg / mL THF, 1.00 mg / mL heptaneSample solution 200 mg sample dissolved in 1 mL DMF

[0142] Organic impurities in vidofludimus (5) and vidofludimus calcium (6) were determined by HPLC using the following chromatographic conditions:Column Phenomenex Synergi Fusion RP 80 A 250 x 4.6 mm; 4 pm or equivalentSecurity guard Phenomenex Synergi Fusion RP 4 x 3.0 mm or equivalent (as required)Eluent A 5 mM KH2PO4, pH 1.5Eluent B Acetonitrile (ACN)Detector UV / VIS, 262 nm;238 nm for the related substance 4-bromo-2-fluoroaniline (2)Example 1 - Vidofludimus (5) small scale synthesis:

[0144] Step 1 to afford 2-fluoro-4-(3-methoxyphenyl)aniline (3)

[0145] 1.00 equivalent (3-methoxyphenyl)boronic acid (1), 1.05 equivalents 4-bromo-2-fluoro-aniline (2), 1.10 equivalents CS2CO3 and Pd(PPh3)4 were mixed in dimethoxy ethane / water (3: 1). The mixture was heated and refluxed for 6 hours. After allowing the mixture to cool to room temperature (25 °C), the organic phase was separated from the aqueous phase. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over MgSCE and the solvent was removed under vacuum. The product was extracted 4 times with diethyl ether charged with HC1 gas. The extract was fdtrated and the obtained crystals were dried in vacuum. The product was stirred with CH2CI2 and saturated NaOH solution (1: 1). The organic phase was separated from the aqueous phase, dried overNa2SO4 and the CH2CI2 was removed under vacuum to afford 2-fluoro-4-(3-methoxyphenyl)aniline (3).

[0146] Step 2 to afford vidofludimus (5)

[0147] 1.0 equivalent 2-fluoro-4-(3-methoxyphenyl)aniline (3) as obtained in step 1 was dissolved in CH2Q2. 1.1 equivalents of 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) were added and the suspension was stirred over night. The filtrate was precipitated and the product was washed with CH2Q2. The product was dried under vacuum to afford vidofludimus (5).

[0148] Overall yield: 27%.Example 2 - boroxine form of the boronic acid starting material:

[0149] A) 3-Methoxyphenylboronic acid (1) (20 g, 1.0 eq.), 4-bromo-2-fluoroaniline (2) (1.05 eq.), Na2CCh (1.13 eq.) and 0.65 mol% Pd (as Noblyst P1079) were charged into EtOH (12.2 vol.) under argon atmosphere. Subsequently, the mixture was heated to reflux for 7 h, cooled to room temperature and kept overnight at this temperature. The mixture was warmed up again to around 70°C and the salts and the catalyst were filtered off over Celite via a pressure filter. The filter materials were subsequently washed with 6.2 vol. hot EtOH. The combined filtrates were concentrated to approximately 12.3 vol. at ambient pressure and subsequently 3.0 vol. water were added at 60 to 70°C Crystallization was initiated upon seeding at about 59°C. After cooling to 4°C in 3 h and additional stirring for 1.5 h at that temperature, the product was isolated as slightly pink crystals with the following impurity profile:

[0150] B) The procedure was performed as outlined in Example 2A) except using different starting material for the 3 -methoxyphenyl boronic acid (1) and performing the reaction for 6 h as outlined below to afford product (3) with the following characteristics according the last in-process control:

[0151] This example demonstrates that the free 3-methoxyphenylboronic acid (1) yielded the product in comparable purity to its boroxine (!').Example 3 - inert gas atmosphere:

[0152] The procedure was performed as outlined in Example 2A) except performing the reaction under A) argon or B) air in EtOH (9.5 vol.) at 80°C for 6 h as outlined below to afford intermediate (3) with the following characteristics according the last in-process control:

[0153] This example demonstrates that the reaction surprisingly seems to be robust also in air.Example 4 - alternative bases:

[0154] The procedure was performed as outlined in Example 2A) except using a different base. The progress of the reaction was monitored and afforded intermediate (3) with the following characteristics according the last in-process control:

[0155] Carbonates as base produces inevitably gaseous CO2 during the reaction. Although the rate seems to be slow and manageable on production scale, KOH was evaluated as alternative base that produces no gaseous by-products. The reaction was also run on screening-size (3 g 3 -methoxyphenyl - boronic acid (1)) and the progress was monitored. As in all screening reactions, the largest difference was observed at the beginning of the reaction until approximately two hours. With KOH as base, the highest initial conversion during development was observed (90.8%-a / a after 0.5 h), however, a drawback of KOH is the formation of impurity B (dimethoxybiphenyl) to a larger extent. Further on, the material stability of an enamel reactor towards KOH in refluxing EtOH is probably not given. Nevertheless, this series of experiments seems to indicate that the strength of the base could play a role in the reaction kinetics.

[0156] The benefit of shorter reaction times is desirable on production. Thus, K2CO3 was evaluated and surprisingly, the reaction was almost as fast as with KOH and the purity profile was even better than with Na2COs. It seems possible that the conversion criterion of >97%-a / a is reachable within 8 h.Example 5 - control over gas evolution:

[0157] The procedure was performed as outlined in Example 2A) except using K2CO3 as base. All reagents, except for 3-methoxyphenylboronic acid (1) were pre-charged in EtOH (5.9 vol.) and heated to reflux. 3-Methoxyphenylboronic acid (1) (1.02 eq. with regard to 4-bromo-2-fluoro-aniline (2)) were dissolved in EtOH (1.5 vol.) and added at reflux during 2 h. The progress ofthe reaction was monitored and afforded product (3) with the following characteristics according the last in-process control:

[0158] The gas evolution during the reaction had to be considered for production . Therefore, the amount of liberated gas was determined in a 71-g -experiment (based on 4-bromo-2-fluoroaniline (2)). K2CO3was used as base in this experiment. All reagents were charged and subsequently heated to reflux. It was observed, that gas evolution only started close to reflux but was smooth over the entire reaction time (in sum 3 L of gas volume was formed). There was only a little steeper increase when reaching reflux. Whereas this behavior would have been feasible in pilot plant during the first campaign the gas evolution could still be an issue on production scale in case larger amounts of product would be required. In order to achieve a better control over the gas evolution the addition of 3-methoxyphenylboronic acid (1) as solution in ethanol was evaluated in an experiment. Therefore, 3-methoxyphenylboronic acid (1) (1.02 eq. with regard to 4-bromo-2 -fluoro-aniline (2)) were dissolved in EtOH (1.5 vol.) and added at reflux during 2 h. After additional 6 h at reflux all 4-bromo-2-fluoro-aniline (2) was consumed (Example 5). The in-process control purity was almost identical to an experiment that was conducted in full-batch mode (Example 4C)) thus the addition of 3-methoxyphenylboronic acid (1) as solution was possible without impact on the downstream processing and was employed for the final process to be able to transfer the process to all scales.Example 6 - Vidofludimus (5) large scale synthesis:

[0159] Step 1 to afford 2-fluoro-4-(3-methoxyphenyl)aniline (3)

[0160] 1.00 equivalent (3-methoxyphenyl)boronic acid (1), 1.05 equivalents 4-bromo-2-fluoro-aniline (2), 1.10 equivalents Na2COs and PdO / C were mixed in ethanol at 25 °C. The mixture was heated and refluxed for 20 hours at 78±5°C under vigorous stirring. Ethanol was charged and the temperature was adjusted to 75°C. The hot solution was filtered and the filter was washed with heated ethanol. The filtrate was concentrated at 78°C. Water was added and the slurry was cooled to 0±3°C. After filtration the crystals were washed with water and cooled ethanol. The product was dried at 60°C under reduced pressure to afford 2-fluoro-4-(3-methoxyphenyl)aniline (3).

[0161] Step 2 to afford vidofludimus (5)

[0162] 1.0 equivalent 2-fluoro-4-(3-methoxyphenyl)aniline (3) as obtained in step 1 was dissolved in THF. The solution was heated to 64±4°C and 1.1 equivalents of 1 -cyclopentene- 1, 2 -dicarboxylic anhydride (4) were added within 40 minutes. The solution was stirred for 4 hours at 64±4°C. The solution was cooled to 5±5°C during 2 hours. The precipitate was filtrated, washed at 5±5°C with THF / heptane (1: 1), and dried at 50°C under reduced pressure to afford vidofludimus (5).

[0163] Overall yield: 81%.

[0164] Compared to Example 1, the yield in Example 6 was increased significantly (81% vs. 27%). Furthermore, subsequent work-up and product isolation were simplified using PdO / C and Na2CO3 as catalyst instead of (PPh3)4Pd and CS2CO3. The purity of the product was increased as well. Experimental details comparing two batches according to Example 1 with three batches according to Example 6 are compiled in the table here below:n.d. = not detectableExample 7 - Vidofludimus (5) modified small scale synthesis:

[0165] Step 1 to afford 2-fluoro-4-(3-methoxyphenyl)aniline (3)

[0166] 1.00 equivalent (3-methoxyphenyl)boronic acid (1), 1.10 equivalents NazCCE and PdO / C were charged in a reactor. 1.05 equivalents 4-bromo-2 -fluoro-aniline (2) and ethanol were additionally charged. The mixture was heated and refluxed for 24 hours. The hot solution was filtered and the filter was washed with heated ethanol. The filtrate was concentrated at 78°C. Water was added and seeding was performed. The slurry was cooled to 0°C. After filtration the crystals were washed with water and ethanol at 0°C. The product was dried under reduced pressure to afford 2-fluoro-4-(3-methoxy- phenyl)aniline (3).

[0167] Optionally, recrystallization from ethanol / water and subsequent drying under reduced pressure can be performed.

[0168] Step 2 to afford vidofludimus (5)

[0169] 1.0 equivalent 2-fluoro-4-(3-methoxyphenyl)aniline (3) as obtained in step 1 was dissolved in THF. The solution was heated to 64±4°C and 1.1 equivalents of 1 -cyclopentene- 1, 2 -dicarboxylic anhydride (4) in THF were added within 40 minutes. The solution was stirred for 4 hours at reflux temperature. During 30 minutes heptane was added at reflux temperature. The solution was cooled to 0°C during 2 hours. The precipitate was filtrated, washed at 0°C with THF / heptane, and dried. The filter cake was heated with ethanol to reflux temperature and agitated for 30 minutes. Water was added and the slurry was agitated for 2 hours at reflux temperature. The suspension was cooled to 25 °C during 2 hours. After filtration the crystals were washed with ethanol. The product was dried at 40°C under reduced pressure to afford vidofludimus (5).Example 8 - Vidofludimus (5) large scale synthesis:

[0170] Step 1 to afford 2-fluoro-4-(3-methoxyphenyl)aniline (3)

[0171] 600 ml absolute ethanol, 100.0 g 4-bromo-2-fluoro-aniline (2) (Mr 190.01 g mol1; 526 mmol), 83.6 g K2CO3 (Mr 138.20 g mol1; 605 mmol) and 8.1 g Pd 10% / C (e.g. Noblyst P1079) were charged to a reactor at a jacket temperature of 20°C. The mixture was heated to reflux temperature. A solution of 81.6 g (3-methoxyphenyl)boronic acid (1) (Mr 151.96 g mol1; 537 mmol) in 160 ml absolute ethanol was added within 2 hours. Subsequently, the mixture was rinsed with 10 ml absolute ethanol, stirred for 7 hours and cooled subsequently to 70°C. A residual content of 4-bromo-2-fluoroaniline (2) amounting to not more than 2% a / a was confirmed (otherwise, the mixture would have been heated to reflux temperature for at least 2 additional hours.

[0172] 290 ml THF and 30 ml deionized water were added at a temperature of 45°C. The temperature was adjusted to 55°C and the mixture was stirred for 15 minutes. After filtration the filter cake was rinsed with a warm mixture (50°C) of 200 ml absolute ethanol and 50 ml THF. The filtrates were combined, concentrated by distillation, and 650 ml distillate were removed. Subsequently, 300 ml distillate were removed and replaced with 300 ml absolute ethanol. A residual content of THF amounting to not more than 30% a / a was confirmed (otherwise, simultaneously 1.0 vol. absolute ethanol would have been added and the same amount of distillate would have been distilled off).

[0173] 330 ml of deionized water were added at 70°C and the temperature was to adjusted to 65°C Seed crystals of 2-fluoro-4-(3-methoxyphenyl)aniline (3) were added and the slurry was stirred for 15 minutes. Start of crystallization / solids was confirmed by visual inspection (otherwise, the temperature would have been lowered in steps of 2°C and seeding would have been repeated).

[0174] The suspension was cooled at a rate of 15°C / hourto 0°C and stirred for 1 hour. The solids were isolated by filtration and the filter cake was washed with a mixture of 100 ml absolute ethanol and 65 ml deionized water, then with 150 ml deionized water and finally with 150 ml absolute ethanol. The material was dried under vacuum at ajacket temperature of 55°C.

[0175] The yield was 99.5 g 2-fluoro-4-(3-methoxyphenyl)aniline (3) equivalent to 87%.

[0176] Step 2 to afford vidofludimus (5)

[0177] A solution of 50.0 g 2-fluoro-4-(3-methoxyphenyl)aniline (3) (Mr 217.24 g mol1; 230 mmol) in 250 ml THF at 20°C was polished into a reactor. The filter was rinsed with 40 ml THF and heated to 60°C. A solution of 15.9 g 1 -cyclopentene- 1,2 -dicarboxylic anhydride (4) (Mr 138.12 g mol1; 115 mmol) in 31 ml THF was added at 65°C during 15 minutes and the mixture was stirred for 30 minutes. Start of crystallization was confirmed by visual inspection (otherwise, the mixture would have been stirred for additional 15 minutes at 65 °C; in case of repeated failure, 20 mg seed crystals would have been added and the slurry would have been stirred for additional 15 minutes).

[0178] A solution of 17.5 g l-cyclopentene-l,2-dicarboxylic anhydride (4) (Mr 138.12 g mol1; 127 mmol) in 34 ml THF at 65°C was added during 60 minutes. The mixture was rinsed with 5 ml THF and stirred at 60°C for 2 hours. The mixture was cooled to 55°C. A residual content of 2-fluoro-4-(3-meth- oxyphenyljaniline (3) amounting to not more than 1.0% a / a was confirmed (otherwise, the mixture would have been heated to 60°C for additional 30 minutes).

[0179] The suspension was heated to 60°C and 295 ml heptane were added during 30 minutes. The suspension was cooled at a rate of 20°C / hourto 0°C and stirred for 30 minutes. The solids were isolated by filtration and the filter cake was washed with a mixture of 100 ml THF and 100 ml heptane. The material was dried under vacuum at a jacket temperature of 50°C.

[0180] The yield was 76.9 g vidofludimus (5) equivalent to 94%.

[0181] Experimental details comparing a batch according to Example 7, step 1 with seven batches according to Example 8, step 1 are compiled in the table here below:

[0182] Experimental details comparing a batch according to Example 7, step 2 with ten batches according to Example 8, step 2 are compiled in the table here below:

[0183] Example 8 provided a crystalline polymorphic form of Vidofludimus (5) having the following characteristic XRPD peaks (Cu2a irradiation at room temperature): 10.6±0.2 20, 11.3±0.2 20, 14.2±0.2 20, 14.5±0.2 20, 19.8±0.2 20, 20.7±0.2 20, 21.3±0.2 20, 21.6±0.2 20, 22.6±0.2 20, 23.5±0.2 20, 26.H0.2 20, 28.0±0.220, 28.4±0.2 20, and 28.7±0.2 20.

[0184] This polymorphic form was stable under various conditions (aging for 4 weeks in 34 different media or under thermal stress).Example 9 - modified Vidofludimus (5) large scale synthesis:

[0185] The following example was performed on a 100 g scale.

[0186] The maximum jacket temperature was set to 130°C. At a jacket temperature of 10-30°C, 600 ml ethanol abs. (6.0 vol ), 30 ml deionized water (0.3 vol., 3.16 eq.), 100.0 g 4-bromo-2 -fluoraniline (1.0 eq.), 83.6 g K2CO3 (1.15 eq.) and 5.7 g Pd 10% / C Noblyst P1079 (0.0046 eq. Pd; 55% water) were charged to the reactor. Part of the ethanol amount was used for rinsing. All equivalents and relative volumes refer to the employed amount of 4-bromo-2-fluoroaniline. 4-bromo-2 -fluoroaniline was added as a melt.

[0187] The black suspension was heated to 75-85°C (reflux). A solution of 81.6 g 3 -methoxyphenyl - boronic acid (1.02 eq.) in 160 ml ethanol, absolute (1.6 vol.) was added within at least 2 hours. The dropping funnel was subsequently rinsed with 10 ml ethanol, absolute (0.1 vol.). The reaction mixture was stirred for at least 4 hours and subsequently cooled to < 70°C for sampling. Continuous gas evolution was observed (CO2). Conversion and purity were checked by HPLC.

[0188] At 30-60°C 290 ml THF (2.9 vol.) were added and the suspension was subsequently adjusted to 50-60°C (target 55 °C) and stirred for at least 15 minutes. The solids were filtered-off and the reaction flask was rinsed with a warm mixture (40-60°C) of 200 ml ethanol, absolute (2.0 vol.) and 50 ml THF (0.5 vol.). The filtrates were combined with one another. The filter cake was salted for Pd-recovery. The crystallization point of the first filtrate was <30°C.

[0189] The combined filtrates were concentrated by distillation. 620-680 ml (target: 650 ml) distillate were removed and disposed. The target volume of the reaction mixture was 650 ml (6.5 vol.). The solvent composition was checked by GC-HS (THF < 55%-a / a). 410 ml deionized water (4.1 vol.) were added at 65-75 °C and the solution was adjusted to 60-70°C (target: 65 °C). Start of crystallization was visually inspected. The suspension was cooled with 10-20°C / h (target: 15°C / h) to -5-5°C and stirred at this temperature for at least 1 hour. The solids were isolated by filtration. The filter-cake was first washed with a mixture of 100 ml ethanol, absolute (1.0 vol.) and 65 ml deionized water (0.65 vol.; displacement wash), then with 150 ml deionized water (1.5 vol.; slurry wash) and finally with 150 ml ethanol, absolute (1.5 vol.; displacement wash).

[0190] About 112 g product pure ethanol-wet were obtained as a whitish solid. The wet-product was dried under vacuum at 50-60°C (LOD (80°C) < 0.5%-w / w; water < 0.9%-w / w). About 103 6 g of pure dry product were obtained (90% of theory corresponding to 4-bromo-2 -fluoroaniline) as whitish to grey to yellowish to pale brown to pink solid.Example 10 - further modified Vidofludimus (5) large scale synthesis:

[0191] 300 kg absolute ethanol were charged to the reactor at < 30°C and the stirrer was turned on. 70 kg 4-bromo-2 -fluoroaniline (molten at 60-70°C) were charged to the reactor and the feed line was rinsedwith 30 kg absolute ethanol. 58.5 kg K2CO3 powder and 4.0 kg catalyst Pd 10% / C Noblyst P1079 were charged to the reactor at < 30°C. The batch was subsequently heated to 70-85°C (reflux) and 145.6 kg 3-methoxyphenylboronic acid solution in absolute ethanol (39%-w / w) was added from a weighing receptacle in at least 2 hours at reflux followed by a rinse with 6 kg absolute ethanol. The batch was subsequently stirred at reflux for at least 7 hours and then cooled to 50-70°C for IPC sampling. The conversion was controlled.

[0192] After successful IPC 21 kg purified water and 180 kg tetrahydrofuran were charged to the reactor, the batch was adjusted to 50-60°C and stirred for at least 15 minutes. The salts were filtered-off on a mobile pressure filter and the filtrate was transferred to a second reactor. The reactor and the salts on the pressure filter were rinsed with a mixture of 31 kg tetrahydrofuran and 111 kg absolute ethanol that was heated in the reactor to 50-60°C before the rinse. The washed salts were disposed. The filtrate in the second reactor was concentrated at ambient pressure by distillation of 440-470 1 (target: 455 1) distillate. Subsequently, the solvent swap was completed by a distillation at constant volume with 300 1 absolute ethanol. The solvent composition was subsequently controlled by an IPC (sampling at IT = 50- 60°C) with a limit for tetrahydrofuran of not more than 30%-a / a.

[0193] After fulfilled IPC the batch was adjusted to 65-75°C and 231 1 purified water were added at this temperature. The batch was adjusted to 60-70°C with a target of 65°C and seeded with 77 g seed crystals. After holding for at least 15 minutes at this temperature a visual control for crystallization was performed. After the crystallization had started, the batch was cooled to -5 to 5°C within at least 5 hours and then stirred for at least 1 hour at this temperature.

[0194] The product was isolated on a pressure filter and the filter cake was consecutively washed with a mixture of 46 kg purified water and 55 kg absolute ethanol (displacement), 105 kg purified water (slurry) and 83 kg absolute ethanol. Mother and wash liquors were discarded. The wet product was discharged and analyzed for batch control before it is dried at < 60°C under vacuum. The release testing of the dried product was finally conducted in QC.Example 11 - Vidofludimus calcium (6) small scale and large scale synthesis:

[0195] A reactor was charged with vidofludimus (5). Calcium hydroxide, THF and purified water were added at low concentration (67 vol. eq.). The mixture was warmed to 30°C and the solution was agitated and filtered. The filtrate was rinsed with THF. The solution was concentrated by distillation. Acetone was added and the mixture was stirred at 20°C for 30 minutes. The thus obtained suspension was filtered. The filter cake was washed with acetone and blow dried with N2. The material was dried in vacuum at 45°C. The solid was homogenized to afford vidofludimus calcium (6).

[0196] Optionally, recrystallization including polishing filtration can be performed.Example 12 - Vidofludimus calcium (6) with reduced THF content:

[0197] To the vidofludimus calcium (6) as obtained in Example 9 ethanol was added and the mixture was heated for 1.5 hours. Purified water was added and the mixture was agitated for 2 hours at 85°C. The mixture was cooled to 25°C within 1.5 hours and agitated for 1 hour. After filtration the filter cake was washed with acetone and blow dried. The material was dried in vacuum at 45°C for 16 hours. The solid was homogenized to afford vidofludimus calcium (6).

[0198] Experimental details comparing five batches according to Example 11 with three batches according to Example 12 are compiled in the table here below:n.d. = not detectableExample 13 - Vidofludimus calcium (6) large scale synthesis:

[0199] 50.0 g vidofludimus (5) (Mr 355.36 g mol1; 141 mmol) as obtained in Example 8 were suspended in 225 ml DMSO at a jacket temperature of 35°C. The suspension was stirred at 35°C for 15 minutes and 25 ml deionized water were added at 35°C. 5.5 g calcium hydroxide (Mr 74. 10 g mol1; 74 mmol) were added at 35°C and the mixture was stirred for 20 minutes. 3.8 g charcoal were added and the mixture was stirred for 2 hours at 25°C. The mixture was heated to 50°C and filtrated. The filter was rinsed with 50 ml DMSO. At 50°C 138 ml absolute ethanol, 25 ml deionized water and seed crystals of vidofludimus calcium (6) were added. The suspension was stirred for 60 minutes. Start of crystallization was confirmed by visual inspection (otherwise, further seed crystals would have been added at 45 °C and the slurry would have been stirred for additional 60 minutes).

[0200] 250 ml deionized water were added during 4 hours at 50°C. The mixture was cooled to 20°C at a rate of 20°C / hour and stirred for 30 min. The solids were isolated by filtration. The filter cake waswashed with 3 x 100 ml absolute ethanol. The product was dried under vacuum at a jacket temperature of 50°C.

[0201] The yield was 53.5 g vidofludimus calcium (6) equivalent to 97%. XRPD analysis revealed that the polymorph of vidofludimus calcium (6) was polymorph A as disclosed in WO 2019 / 175396.

[0202] Experimental details comparing a batch according to Example 12 with five batches according to Example 13 are compiled in the table here below:n.d. = not detectableComparative Example:

[0203] In WO 2019 / 175396 aprocess with the following characteristics is described (claim 15): a) adding to a mixture of calcium hydroxide and free acid of a compound according to formula I or a solvate and / or a hydrate thereof an organic solvent and water b) stirring the suspension obtained in step a) until a solution is obtained, c) at least partially evaporating said organic solvent and water to obtain a suspension of the calcium salt of a compound according to formula I or a solvate and / or a hydrate thereof d) adding an aprotic organic solvent, fully mixable with water to said suspension of the calcium salt of a compound according to formula I or a solvate and / or a hydrate thereof obtained in step c) e) stirring the suspension obtained in step d), f) recovering the calcium salt of a compound according to formula I or a solvate and / or a hydrate thereof from the mixture obtained in step e), and g) washing the calcium salt of a compound according to formula I or a solvate and / or a hydrate thereof obtained in step f) with the aprotic organic solvent mentioned in step d).h) slurring the isolated calcium salt a compound according to formula I or a solvate and / or a hydrate thereof obtained in step g) in an alcoholic solvent at 15 - 80°C.I) adding water to the slurry obtained in step h) at 15 - 85 °C j) recovering the calcium salt of a compound according to formula I or a solvate and / or a hydrate thereof from the mixture obtained in step e), and k) washing the calcium salt of a compound according to formula I or a solvate and / or a hydrate thereof obtained in step j) with the aprotic organic solvent mentioned in step d).

[0204] Comparative Example exemplifies experimental details for such process:

[0205] The reactor was charged with 2-((3-fluoro-3'-methoxy-[l,T-biphenyl]-4-yl)carbamoyl)cyclo- pent-l-ene-1 -carboxylic acid (10. 1 kg), Ca(OH)2(1.09 kg) and THF (402.7 kg) at room temperature. To the pale yellow slurry was added purified water (222.2 kg) within approx. 8 min. The yellow color disappeared and a small exotherm of mixing (2-3 °C) was observed. To perform a polish filtration, the slurry was heated to 40 to 60°C until a clear solution was formed, then agitated for 20 to 30 min (already some turbidity was formed) and filtered. The vessel, line and filter was rinsed with THF (36 kg). The above procedure was performed twice with two identical batches. Both filtered solutions were combined and reduced to approx. 400 L in vacuo at T <45°C. To the concentrated warm suspension was added acetone (808 kg). The suspension was cooled down (17-25°C), stirred for additional 1.5 h and filtered. The product on the filter was washed with acetone (96 kg), then blow-dried with nitrogen for 1 h and dried in vacuo at 45°C overnight. The material (19 kg, still containing some THF) was reintroduced in the cleaned reactor vessel, EtOH (228 kg) was added and the white slurry was heated to 75°C under agitation for 1.3 h. Then preheated (70-75°C) water (570 kg) was added over a period of about 50 min, maintaining the temperature between 65 to 70°C. The slurry was agitated at 80°C for 1 h, cooled down to approx. 25°C and stirred for an additional hour at 25°C. The material was filtered, washed with acetone (60 kg) and dried in vacuo at 45°C for 5 d to obtain the target calcium salt (18.6 kg) as a white to off-white solid.

[0206] Analytical characterization by HPLC revealed to following impurity profile: 2-fluoroamline not detected; 4-bromo-2-fluoroaniline <0.004%-w / w; 3-fluoro-3'-methoxy-[l,r-biphenyl]-4-amine <0.004%-w / w; and largest unspecified impurity <0.05%-w / w; residual solvents (GC): acetone <LOQ; EtOH 5607 ppm; THF 218 ppm; elemental impurities (ICP-MS): Pd <1 ppm., other heavy metals <20 ppm.

[0207] Comparison of the former claimed process (WO2019 / 175396, claim 15) according to Comparative Example with Example 13 according to the invention:

[0208] The process according to the invention has substantial differences compared to the process of WO 2019 / 175396 (e.g. claim 15):(i) all solvents are in the non-hazardous ICH class (e g. no THF necessary);(ii) the total volume has been substantially reduced;(iii) fall control over the crystallization allows for a good scalability due to improved filtration properties;(iv) the reslurry to reduce unwanted solvents from the API is no more necessary, as the product fulfills immediately all specifications; and(v) the depletion of potential genotoxic impurities in the process has been quantified in the course of the development.

Claims

Claims:

1. A process for preparation of 2-fluoro-4-(3-methoxyphenyl)aniline (3) comprising or consisting of the steps:(ai) providing (3-methoxyphenyl)boronic acid (1);(a2) providing 4-bromo-2-fluoro-aniline (2);(as) reacting (3-methoxyphenyl)boronic acid (1) and 4-bromo-2-fluoro-aniline (2) to afford 2- fluoro-4-(3-methoxyphenyl)aniline (3):1 2 3; and(34) optionally, isolating 2-fluoro-4-(3-methoxyphenyl)aniline (3).

2. The process according to claim 1, wherein in step (a ) the molar ratio of (3-methoxyphenyl)bo- ronic acid (1) to 4-bromo-2-fluoro-aniline (2) is greater than 1.00; preferably at least 1.01; more preferably within the range from 1.01 to 1.30; still more preferably from 1.01 to 1.05.

3. The process according to claim 1 or 2, wherein in step (ai) (3-methoxyphenyl)boronic acid (1) is provided as a solution or suspension in a solvent; preferably ethanol; more preferably absolute ethanol.

4. The process according to any of the preceding claims, wherein in step (as) 4-bromo-2-fhioro- aniline (2) is provided as a solution or suspension in a solvent; preferably ethanol; more preferably absolute ethanol.

5. The process according to claim 4, wherein the solution or suspension additionally comprises or essentially consists of a catalyst, preferably a Suzuki coupling catalyst, and optionally a base.

6. The process according to claim 4 or 5, wherein in step (as) (3-methoxyphenyl)boronic acid (1) is added to the solution or suspension.

7. The process according to claim 6, wherein in step (as) (3-methoxyphenyl)boronic acid (1) is added continuously or in portions during a time period of at least 30 minutes; preferably at least 60 minutes; more preferably at least 90 minutes.

8. The process according to any of the preceding claims, wherein step (as) is performed in the presence of a catalyst, preferably a Suzuki coupling catalyst, comprising palladium; preferably selected from PdO / C, Pd / C and Pd(PPhs)4; more preferably PdO / C.

9. The process according to any of the preceding claims, wherein step (as) is performed in the presence of a base; preferably an inorganic base; more preferably a carbonate; still more preferably an alkali metal carbonate; yet more preferably an alkali metal carbonate selected from K2CO3, Na2CC>3 and CS2CO3; even more preferably K2CO3.

10. The process according to claim 9, wherein in step (as) the molar ratio of (3-methoxyphenyl)bo- romc acid (1) to the base is greater than 1.00; preferably at least 1.05; more preferably at least 1.10; still more preferably within the range of from 1.10 to 1.50; yet more preferably from 1.10 to 1.20.

11. The process according to any of the preceding claims, wherein step (as) is performed in a solvent comprising or essentially consisting of ethanol, dimethoxy ethane, water, or any mixture thereof; preferably ethanol; more preferably absolute ethanol.

12. The process according to any of the preceding claims, wherein step (as) is performed under reflux temperature.

13. The process according to any of the preceding claims, wherein step (as) comprises crystallization of 2-fluoro-4-(3-methoxyphenyl)aniline (3); preferably cooling crystallization.

14. The process according to claim 13, wherein crystallization is performed from a solution in a solvent comprising or essentially consisting of ethanol, THF, water, or any mixture thereof; preferably from a mixture of ethanol, THF and water.

15. The process according to claim 13 or 14, wherein crystallization is induced by adding seed crystals of 2-fluoro-4-(3-methoxyphenyl)aniline (3).

16. The process according to any of claims 13 to 15, wherein the crystals are isolated, preferably by filtration, and dried, preferably at elevated temperature and / or under reduced pressure.

17. The process according to any of the preceding claims, wherein step (ai) comprises evaporation of solvent.

18. A process for preparation of vidofhidimus (5) comprising or consisting of the steps:(bi) providing 2-fluoro-4-(3-methoxyphenyl)aniline (3);(b2) providing l-cyclopentene-l,2-dicarboxylic anhydride (4);(b ) reacting 2-fluoro-4-(3-methoxyphenyl)aniline (3) with 1 -cyclopentene- 1,2-dicarboxylic anhydride (4) to afford vidofludimus (5):(b4) optionally, isolating the vidofludimus (5).

19. The process according to claim 18, wherein step (bi) comprises or consists of the process according to any of claims 1 to 15.

20. The process according to claim 18 or 19, wherein in step (bi) the molar ratio of 1-cyclopentene- 1,2-dicarboxylic anhydride (4) to 2-fluoro-4-(3-methoxyphenyl)aniline (3) is greater than 1.00; preferably at least 1.01; more preferably at least 1.02; still more preferably within the range of from 1.02 to 1.30; yet more preferably from 1.02 to 1.10.

21. The process according to any of claims 18 to 20, wherein in step (b2) 1 -cyclopentene- 1,2-dicar- boxylic anhydride (4) is provided as a solution or suspension in a solvent; preferably THF.

22. The process according to any of claims 18 to 21, wherein in step (bi) 2-fluoro-4-(3-methoxy- phenyl)aniline (3) is provided as a solution or suspension in a solvent; preferably THF.

23. The process according to claim 22, wherein in step (b;,) l-cyclopentene-l,2-dicarboxylic anhydride (4) is added to the solution or suspension.

24. The process according to claim 23, wherein in step (ba) l-cyclopentene-l,2-dicarboxylic anhydride (4) is added continuously or in portions during a time period of at least 5 minutes; preferably at least 10 minutes; more preferably at least 15 minutes.

25. The process according to claim 22 or 23, wherein in step (bs) a first portion of 1-cyclopentene- 1,2-dicarboxylic anhydride (4) is added to the solution or suspension; and wherein after crystallization of vidofludimus (5) has commenced, a second portion of l-cyclopentene-l,2-dicarboxylic anhydride (4) is added to the suspension.

26. The process according to any of claims 18 to 25, wherein step (b,) is performed in a solvent comprising or essentially consisting of THF.

27. The process according to any of claims 18 to 26, wherein step (b?) is performed at a temperature of from 50°C to 66°C; preferably from 55°C to 65°C.

28. The process according to any of claims 18 to 27, wherein step (b4) comprises crystallization of vidofludimus (5); preferably cooling crystallization.

29. The process according to claim 28, wherein crystallization of vidofludimus (5) is performed from a solution in a solvent comprising or essentially consisting of THF, heptane, or a mixture thereof; preferably from a mixture of THF and heptane.

30. The process according to claim 28 or 29, wherein crystallization is induced by adding seed crystals of vidofludimus (5).

31. The process according to any of claims 28 to 30, wherein the crystals are isolated, preferably by filtration, and dried, preferably at elevated temperature and / or under reduced pressure.

32. The process according to any of claims 18 to 31, wherein step (b4) comprises evaporation of solvent.

33. A process for preparation of vidofludimus calcium (6) comprising or consisting of the steps:(ci) providing vidofludimus (5);(C2) providing a calcium salt;(eg) reacting vidofludimus (5) with the calcium salt to afford vidofludimus calcium (6); and(C4) optionally, isolating vidofludimus calcium (6).

34. The process according to claim 33, wherein step (ci) comprises or consists of the process according to any of claims 18 to 32.

35. The process according to claim 33 or 34, wherein in step (C3) the molar ratio of calcium salt to vidofludimus (5) is greater than 0.50; preferably at least 0.51; more preferably within the range of from 0.51 to 0.80; still more preferably from 0.51 to 0.60.

36. The process according to any of claims 33 to 35, wherein the calcium salt comprises or essentially consists of Ca(OH)2.

37. The process according to any of claims 33 to 36, wherein in step (m) vidofludimus (5) is provided as a solution or suspension in a solvent; preferably DMSO, water or a mixture thereof.

38. The process according to claim 37, wherein in step (C3) calcium salt is added to the solution or suspension.

39. The process according to any of claims 33 to 38, wherein step (C3) is performed in a solvent comprising or essentially consisting of DMSO, water or a mixture thereof; preferably a mixture of DMSO and water.

40. The process according to any of claims 33 to 39, wherein(i) step (C3) is performed in the presence of an adsorbent; or(ii) after step (ca) an adsorbent is added.

41. The process according to claim 40, wherein the adsorbent comprises or essentially consists of charcoal.

42. The process according to any of claims 33 to 41, wherein step (C4) comprises crystallization of vidofludimus calcium (6); preferably cooling crystallization.

43. The process according to claim 42, wherein crystallization of vidofludimus calcium (6) is performed from a solution in a solvent compnsing or essentially consisting of DMSO, water, ethanol, or a mixture thereof; preferably from a mixture of DMSO, water and ethanol.

44. The process according to claim 42 or 43, wherein crystallization is induced by adding seed crystals of vidofludimus calcium (6).

45. The process according to any of claims 42 to 44, wherein the crystals are isolated, preferably by fdtration, and dried, preferably at elevated temperature and / or under reduced pressure.

46. The process according to any of claims 33 to 45, wherein step (04) comprises evaporation of solvent.

47. A composition essentially consisting of vidofludimus (5), which has a residual content of palladium, determined by ICP-MS, amounting to (i) at least 0.01 ppm and (ii) at most 10 ppm; preferably at most 5.00 ppm; more preferably less than 2.00 ppm; still more preferably at most 1.50 ppm; yet more preferably at most 1.00 ppm; even more preferably at most 0.80 ppm; in each case relative to the total weight of vidofludimus (5).

48. A composition essentially consisting of vidofludimus (5), which has a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]carbamoyl]cyclopentene-l-carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; in each case relative to the total weight of vidofludimus (5); preferably wherein the composition has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppm.

49. The composition according to claim 47 or 48, which has a content of vidofludimus (5) of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99.00 wt.-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt-%; in each case relative to the total weight of the composition.

50. The composition according to any of claims 47 to 49, which has one or more of the following residual contents of starting materials or byproducts, in each case determined by HPLC and in each case relative to the total weight of vidofludimus (5):(i) 2-fluoroaniline: <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt.-%; and / or(ii) 2-fluoro-4-(3-methoxyphenyl)aniline (3): <0.003 wt.-%; preferably <0.002 wt.-%; and / or(iii) 4-bromo-2-fluoroaniline (2): <0.004 wt.-%; preferably <0.003 wt.-%; more preferably<0.002 wt.-%; and / or(iv) cy clopent- l-ene-l,2-dicarboxylic acid: <0.15 wt.-%; preferably <0.05 wt.-%; more preferably <0.016 wt.-%; still more preferably <0.014 wt.-%.

51. The composition according to any of claims 47 to 50, which has a total content of impurities of at most 0.5 wt.-%, in each case determined by HPLC and in each case relative to the total weight of vidofludimus (5).

52. The composition according to any of claims 47 to 51, which has a water content of at most 5.0 wt.-%, determined by Karl Fischer titration and relative to the total weight of vidofludimus (5).

53. The composition according to any of claims 47 to 52, which has one or more of the following residual contents of solvents, in each case determined by GC and in each case relative to the total weight of vidofludimus (5):(i) ethanol: <5000 ppm; preferably <500 ppm; more preferably <50 ppm; still more preferably <10 ppm; and / or(ii) heptane: <5000 ppm; preferably <500 ppm; more preferably <160 ppm; and / or(iii) THF: <720 ppm; preferably <500 ppm; more preferably <400 ppm; still more preferably <300 ppm; and / or(iv) DMSO: <5000 ppm.

54. The composition according to any of claims 47 to 53, which has one or more of the following residual contents of metals, in each case determined by ICP-MS and in each case relative to the total weight of vidofludimus (5):(i) arsenic (As): <1.5 ppm; and / or(ii) cadmium (Cd): <0.5 ppm; and / or(iii) lead (Pb): <0.5 ppm; and / or(iv) mercury (Hg): <3.0 ppm; and / or(v) cobalt (Co): <5.0 ppm; and / or(vi) nickel (Ni): <20 ppm; and / or(vii) vanadium (V): <10 ppm.

55. The composition according to any of claims 47 to 54, which has characteristic XRPD peaks (Cuza irradiation at room temperature) at 10.6±0.2 20, 11.3±0.2 20, 14.2±0.2 20, 21.3±0.2 20, 21.6±0.220, and 26.1±0.2 20.

56. The composition according to claim 55, which has additionally one or more characteristic XRPD peaks (Cu2« irradiation at room temperature) selected from 14.5±0.2 26, 19.8±0.2 26, 20.7±0.2 26, 22.6±0.2 26, 23.5±0.2 26, 28.0±0.2 26, 28.4±0.226, and 28.7±0.2 26.

57. The composition according to any of claims 47 to 56, which is obtainable by the process according to any of claims 18 to 32.

58. A composition essentially consisting of vidofludimus calcium (6), which has a content of vidoflu- dimus calcium (6) of at least 98.00 wt.-%; preferably at least 98.50 wt.-%; more preferably 99.00 wt.-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt-%; in each case relative to the total weight of the composition.

59. The composition according to claim 58, which has a residual content of palladium, determined by ICP-MS and in each case relative to the total weight of vidofludimus calcium (6), amounting to (i) at least 0.01 ppm and (ii) at most 10 ppm; preferably at most 5.00 ppm; more preferably less than 2.00 ppm; still more preferably at most 1.50 ppm; yet more preferably at most 1.00 ppm; even more preferably at most 0.80 ppm.

60. The composition according to claim 58 or 59, which has a content of arsenic (As), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6), of 0.00 to <1.5 ppm.

61. The composition according to any of claims 58 to 60, which has a content of cadmium (Cd), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <0.5 ppm.

62. The composition according to any of claims 58 to 61, which has a content of lead (Pb), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <0.5 ppm.

63. The composition according to any of claims 58 to 62, which has a content of mercury (Hg), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <3.0 ppm.

64. The composition according to any of claims 58 to 63, which has a content of cobalt (Co), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <5.0 ppm.

65. The composition according to any of claims 58 to 64, which has a content of nickel (Ni), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6), of 0.00 to <20 ppm.

66. The composition according to any of claims 58 to 65, which has a content of vanadium (V), determined by ICP-MS and relative to the total weight of vidofludimus calcium (6) of 0.00 to <10 ppm.

67. The composition according to any of claims 58 to 66, which has a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]carbamoyl]cyclopentene-l-carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt.-%, more preferably not more than 0.001 wt.-%; in each case relative to the total weight of vidofludimus calcium (6); preferably wherein the composition has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppm.

68. The composition according to any of claims 58 to 67, which has a residual content of 2-fluoroan- iline, determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt.-%.

69. The composition according to any of claims 58 to 68, which has a residual content of 2-fluoro-4- (3-methoxyphenyl)aniline (3), determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.003 wt.-%; preferably <0.002 wt.-%.

70. The composition according to any of claims 58 to 69, which has a residual content of 4-bromo-2- fluoroaniline (2), determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.004 wt.-%; preferably <0.003 wt.-%; more preferably <0.002 wt.-%.

71. The composition according to any of claims 58 to 70, which has a residual content of cyclopent- l-ene-l,2-dicarboxylic acid, determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6), of <0.15 wt.-%; preferably <0.05 wt.-%; more preferably <0.016 wt- %; still more preferably <0.014 wt.-%.

72. The composition according to any of claims 58 to 71, which has a total content of impurities of at most 0.5 wt.-%, in each case determined by HPLC and in each case relative to the total weight of vidofludimus calcium (6).

73. The composition according to any of claims 58 to 72, which has a water content of at most 5.0 wt.-%, determined by Karl Fischer titration and relative to the total weight of vidofludimus calcium (6).

74. The composition according to any of claims 58 to 73, which has a residual content of ethanol, determined by GC and in each case relative to the total weight of vidofludimus calcium (6), of <5000 ppm; preferably <500 ppm; more preferably <50 ppm; still more preferably <10 ppm.

75. The composition according to any of claims 58 to 74, which has a residual content of heptane, determined by GC and in each case relative to the total weight of vidofludimus calcium (6), of <5000 ppm; preferably <500 ppm; more preferably <160 ppm.

76. The composition according to any of claims 58 to 75, which has a residual content of THF, determined by GC and in each case relative to the total weight of vidofludimus calcium (6), of <720 ppm; preferably <500 ppm; more preferably <400 ppm; still more preferably <300 ppm.

77. The composition according to any of claims 58 to 76, which has a residual content of DMSO, determined by GC and relative to the total weight of vidofludimus calcium (6), of <5000 ppm.

78. The composition according to any of claims 58 to 77, which is obtainable by the process according to any of claims 33 to 46.

79. A pharmaceutical composition comprising- (i) the composition according to any of claims 47 to 57 or (ii) the composition according to any of claims 58 to 78; and- at least one pharmaceutically acceptable carrier or excipient.

80. A compound prepared by the method of any one of claims 18-32, wherein the compound is vidofludimus (5) or a pharmaceutically acceptable salt thereof.

81. A compound prepared by the method of any one of claims 18-32, wherein the compound is vidofludimus (5), and wherein vidofludimus (5) has:A) a residual content of palladium, determined by ICP-MS, amounting to (i) at least 0.01 ppm and (ii) less than 2.00 ppm; preferably at most 1.50 ppm; more preferably at most 1.00 ppm; still more preferably at most 0.80 ppm; and / orB) a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]car- bamoyl] cyclopentene- 1 -carboxylic acid) of not more than 0.003 wt.-%, preferably not more than 0.002 wt-%, more preferably not more than 0.001 wt-%; in each case relative to the total weight of vidofludimus (5); preferably wherein the compound has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppmw.

82. The compound according to claims 80 and 81, which has a content of vidofludimus (5) of at least 98.00 wt.-%; preferably at least 98.50 wt-%; more preferably 99.00 wt.-%; still more preferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt.-%; in each case relative to the total weight of the compound.

83. The compound according to claims 80 to 82, which has characteristic XRPD peaks (Cu2« irradiation at room temperature) at 10.6±0.2 20, 11.3±0.2 20, 14.2±0.2 20, 21.3±0.2 20, 21.6±0.2 20, and 26.1±0.2 20.

84. The compound according to claim 83, which has additionally one or more characteristic XRPD peaks (Cu2« irradiation at room temperature) selected from 14.5±0.2 20, 19.8±0.2 20, 20.7±0.2 20, 22.6±0.2 20, 23.5±0.2 20, 28.0±0.2 20, 28.4±0.220, and 28.7±0.2 20.

85. A compound prepared by the method of any one of claims 33-46, wherein the compound is vidofludimus calcium (6).

86. A compound prepared by the method of any one of claims 33-46, wherein the compound is vidofludimus calcium (6), and wherein the vidofludimus calcium (6) has:A) a residual content of palladium, determined by ICP-MS, amounting to (i) at least 0.01 ppm and (ii) less than 2.00 ppm; preferably at most 1.50 ppm; more preferably at most 1.00 ppm; still more preferably at most 0.80 ppm; and / orB) a residual content of impurity (E) (2-[[4-(4-amino-3-fluoro-phenyl)-2-fluoro-phenyl]car- bamoyl] cyclopentene- 1 -carboxylic acid) of not more than 0.003 wt-%, preferably not more than 0.002 wt-%, more preferably not more than 0.001 wt-%; in each case relative to the total weight of vidofludimus calcium (6); preferably wherein the composition has a residual content of impurity (E) above the detection limit of the HPLC, more preferably at least 1 ppmw.

87. The compound according to claims 85 and 86, which has a content of vidofludimus calcium (6) of at least 98.00 wt.-%; preferably at least 98.50 wt-%; more preferably 99.00 wt-%; still morepreferably at least 99.50 wt.-%; yet more preferably at least 99.60 wt.-%; even more preferably at least 99.70 wt.-%; in each case relative to the total weight of the compound.

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